1. Field of the Invention
The invention relates to a calcium phosphate cement composition that comprises two components and to a dual chamber device having a separator between the two chambers that can be removed to allow for mixing of the composition.
2. Description of the Related Art
Most commercial cements are in the form of two components: a solid component (i.e. a powder or powder mixture) and a liquid component. These cements have a good shelf-life stability provided the two components are kept separate. To initiate the setting/hardening reaction, the two components (solid+liquid) must be mixed just prior to the application. Indeed, as soon as the liquid contacts the solid, the setting reaction starts. Generally, the paste obtained by mixing the liquid with the solid component must be transferred from the mixing container into an injection system. In other words, handling is not very good (the powder and the liquid need to be mechanically mixed; the resulting paste must be transferred into an injection system; the calcium phosphate cement (CPC) paste needs to be injected within a short time after powder-liquid mixing).
From WO 03/041753 (Lemaitre) a CPC is known based on the mixture of two calcium phosphate pastes. The main advantage of this prior art cement relies in the possibility to mix the two pastes by injection through a static mixer. Provided the two pastes can react together (e.g. via an acid-base reaction), it is possible to design a CPC that is mixed during injection. In other words, there is no need to mix a powder with a liquid or to transfer the resulting paste into an injection system. Lemaitre disclosed three examples of CPC formulations. In example 1, the end product of the reaction was a so-called “brushite” (dicalcium phosphate dihydrate; CaHPO4.2H2O). Both components were stable during years. In the second example, a paste consisting mainly of tetracalcium phosphate (TetCP; Ca4(PO4)2O) was mixed with a paste consisting mainly of dicalcium phosphate (CaHPO4). Whereas the second paste was most likely stable during years, there were no scientific data showing that the first phase would remain stable during years. Considering the very large reactivity of TetCP the paste stability is limited to a few minutes. The third example is devoted to CPCs made of alpha-tricalcium phosphate (alpha-TCP). Contrary to the statement made in Lemaitre, it was not possible to reproduce the claimed results: α-TCP reacted within a few hours/days with water to form calcium-deficient hydroxyapatite (CDHA).
What is therefore needed are calcium phosphate compositions which can be safely stored for years and still retain their full reactivity when mixed.
In other words, the first paste (“Component A”) consisting of a mixture of reactive calcium phosphate powder and water must contain a reaction inhibitor to prevent the transformation of the reactive calcium phosphate powder into an apatite phase. Furthermore, the second paste (“Component B”) must contain a substance able to activate the reaction of the reactive calcium phosphate powder present in the first paste, a so-called “activator”.
The invention solves this task with a calcium phosphate cement composition comprising two components and with a dual-chamber device having a separator between the two chambers that can be removed to allow for mixing of the composition.
Component A preferably comprises a reactive calcium phosphate powder (tetracalcium phosphate (TetCP), Ca4(PO4)2O, α-tricalcium phosphate (α-TCP), amorphous calcium phosphate (ACP), Ca3(PO4)2.nH2O, water, and a reaction inhibitor. The reaction inhibitor can either inhibit the dissolution of the reactive calcium phosphate powder, or preferably the precipitation of an apatite. Here, the term “apatite” is used to designate various compounds or mixtures thereof such as hydroxyapatite (HA); Ca5(PO4)3OH), calcium-deficient hydroxyapatite (CDHA); 2Ca9(HPO4)(PO4)5OH), carbonated apatite, fluorapatite, chlorapatite, oxyapatite, or ion-substituted apatite. These compounds can have slightly different compositions but all have the same crystallographic structure. As a result, all inhibitors of e.g. hydroxyapatite can be used to inhibit other apatite forms, such as e.g. carbonated apatite. Typical substances that can be used include anions like carboxylated compounds (e.g. citrate, polyacrylates), pyrophosphates and bisphosphonates, as well as cations like Mg or Zn. More complex molecules like peptides and proteins can also be used. All these substances can be quoted to be “inhibitors”. However, it has surprisingly become apparent that only Mg2+, Sr2+ or Ba2± cations can be considered to be adequate inhibitors for the present invention.
The inhibitor concentration is important. As the action of inhibitors is related to their adsorption on active sites (e.g. dislocations) of calcium phosphate particles, the inhibitor concentration must be large enough to block all active sites: a concentration superior to 0.01M of the inhibitor cations is required.
Contrary to amorphous calcium phosphate, α-TCP is produced using a high-temperature thermal treatment followed by milling. During the milling step, part of the powder becomes amorphous. This amorphous part is highly reactive. It has been possible to show that this amorphous part could be removed by a thermal treatment in the range of 400 to 700° C. Therefore, α-TCP powder is preferably calcined to keep a high calcium phosphate-water paste stability during shelf-life.
Component B must contain a substance able to anneal the effect of the inhibitor present in component A. Throughout the patent it is called the “activator”. As the action of inhibitors is related to their adsorption on active sites of calcium phosphate particles, the activator must be able to displace the inhibitor without itself inhibiting the CPC reaction. Surprisingly observations showed that Ca2+ cations can displace Mg2+, Sr2+ or Ba2+ cations and activate the reaction. The effect is dependent on the concentration, which has to be at least 0.01 M and preferably there should be at least 2 times, preferably 5 times more Ca2+ cations than Mg2+, Sr2+ or Ba2+ cations.
The advantage of the calcium phosphate cement composition according to the invention is its prolonged storage capability.
Further advantageous embodiments of the invention can be commented as follows:
Particularly good results were obtained when the inhibitor cations were selected from Mg2+ only or from Sr2+ only.
The ratio of component A to component B is preferably such that upon mixing of the two components the molar ratio of Ca2+ ions/inhibitor cations in the mixture is superior to 2, preferably superior to 5.
The calcium phosphate powder to be used with the calcium phosphate cement composition is preferably alpha-tricalcium phosphate or amorphous calcium phosphate (ACP).
Purposefully the a-tricalcium phosphate powder is obtained by calcination at a temperature in the range of 400° C. to 700° C. for at least 10 minutes. This treatment leads to a reduction of the a-tricalcium phosphate powder reactivity with water in the absence of an inhibitor.
The concentration of the inhibitor cations in component A is preferably equal to or larger than 0.05 M, preferably larger than 0.1 M.
Purposefully component B comprises highly soluble calcium salts with a solubility superior to 0.5 M, preferably superior to 1.0 M.
In special embodiments component B comprises one or more of the following calcium salts:
calcium chloride (anhydrous: CaCl2, monohydrate: CaCl2.H2O, dihydrate: CaCl2.2H2O, or hexahydrate: CaCl2.6H2O), dicalcium phosphate dihydrate (CaHPO4.2H2O; DCPD), calcium sulphate dihydrate (CaSO4.2H2O; CSD), calcium sulphate hemihydrate (CaSO4.½H2O; CSH), calcium sulphate (CaSO4), calcium nitrate, calcium acetate (anhydrous: Ca(C2H3O2)2, monohydrate: Ca(C2H3O2)2.H2O, or dihydrate Ca(C2H3O2)2.2H2O), calcium citrate (Ca3(C6H5O7).4H2O), calcium fumarate (CaC4H2O4.3H2O), calcium glycerophosphate (CaC3H5(OH2)PO4), calcium lactate (Ca(C3H5O3)2.5H2O), calcium malate (dl-malate: CaC4H4O5.3H2O, l-malate: CaC4H4O5.2H2O, or malate dihydrogen: Ca(HC4H4O5)2.6H2O), calcium maleate (CaC4H2O4.H2O), calcium malonate (CaC3H2O4.4H2O), calcium oxalate (CaC2O4), calcium oxalate hydrate (CaC2O4.H2O), calcium salicylate.(Ca(C7H5O3)2.2H2O), calcium succinate (CaC4H6O4.3H2O), calcium tartrate (d-tartrate: CaC4H4O6.4H2O; dl-tartrate: CaC4H4O6.4H2O; mesotartrate: CaC4H4O6.3H2O), and calcium valerate (Ca(C5H9O2)2).
Preferably the volume ratio of the two components A/B is equal to or larger than 4 and is preferably lower than 12.
In a further embodiment the concentration of Ca2+ ions in component B is superior to 0.5 M.
In a further embodiment component B comprises a calcium phosphate powder, in particular an apatite, preferably a pure hydroxyapatite, an ion-substituted hydroxyapatite such as Si- or Sr-substituted apatite, or a Ca-deficient hydroxyapatite (CDHA). These compounds prevent phase separation (solid-liquid) during injection because when the particles are very small, it is more difficult for the liquid to flow between the particles to reach phase separation.
In a special embodiment the quantity of calcium phosphate powder in component B is equal to or larger than 0.4 g/mL, preferably larger than 1.0 g/mL
In a further embodiment the particles of the calcium phosphate powder are nanocrystals, preferably with a mean diameter of 100 nm. The resulting water-nanocrystals pastes have exhibited surprisingly good rheological properties, being easily injectable and cohesive, i.e. the paste does not easily disintegrate when injected into a liquid, such as blood.
In a further embodiment component A or B or both comprise a small amount of water soluble polymer. This additive generates a gel with a markedly increased liquid viscosity which prevents phase separation (solid-liquid) during injection. The polymer can be chosen from the group of: (i) hyaluronan, preferably sodium hyaluronate or hyaluronic acid); (ii) chondroitin sulphate; (iii) cellulose derivatives, preferably hydroxypropylmethyl cellulose or methylcellulose; (iv) polyvinylpyrrolidone; (v) N-methyl-2-pyrrolydone or (vi) dimethylsiloxane; (vii) alginate, (viii) chitosan, (ix) gelatine, (x) collagen. The amount of polymer is purposefully at least 0.1 weight %, preferably at least 0.3 weight %. The amount of polymer purposefully is at most 3.0 weight %, preferably at most 2.0 weight %.
The calcium phosphate cement can further comprise a radiopacifier, chosen from the following groups: (i) iodine based solutions, preferably iohexol, iodixanol and ioversol; (ii) metallic powders, preferably Ta; or (iii) ceramics, preferably tungsten carbide, bismuth oxide or zirconium oxide.
The calcium phosphate-to-liquid weight ratio upon mixing of components A and B is preferably equal to or larger than 2.
Purposefully the pH of component B is equal to or lower than 6, preferably lower than 5. The pH of component B may be adjusted using a weak acid, preferably using acetic acid, formic acid, lactic acid, citric acid, and propionic acid. The concentration of the weak acid in component B is purposefully equal to or larger than 0.1 M, preferably larger than 0.2 M.
The pH of component A is purposefully superior to 8, preferably superior to 9.
In a special embodiment the alpha-tricalcium phosphate has a purity of more than 80%, preferably of more than 90%. The alpha-tricalcium phosphate is preferably contaminated with apatite.
In a further embodiment the alpha-tricalcium phosphate has a specific surface area (SSA) larger than 0.5 m2/g, preferably larger than 2.0 m2/g.
The dual chamber device according to the invention has two separate chambers CA and CB the content of which can be mixed upon removing the separation between the two chambers and wherein chamber CA contains component A and chamber CB contains component B of the calcium phosphate cement composition according to the invention. Preferably the volume ratio A/B of component A to component B in the dual chamber device is in the range of 4:1 and 12:1.
The following examples clarify the invention further in more detail.